Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as agents for control of hypertension, congestive heart failure, and hyperaldosteronism.
European Application No. 86/106458 covers certain renininhibiting N-(acyldipeptidyl)-aminoglycols of the formula ##STR1## wherein R.sub.1 is alkoxy containing one to six carbon atoms or lower alkyl containing one to six carbon atoms; R.sub.2 is benzyl or napthylmethyl, R.sub.3 is lower alkyl containing one to six carbon atoms or imidazolemethyl; R.sub.4 is benzyl, R.sub.5 is hydrogen or lower alkyl and n is 0. These compounds are useful as renin inhibitors.
European Application No. 87/100424 covers renin inhibiting peptidyl-amino-diols of formula ##STR2## wherein A is a substituent; W is C.dbd.O or CHOH; U is CH.sub.2 or NR.sub.2 ; R.sub.1 is lower alkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, .alpha.,.alpha.-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is lower alkyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, lower alkenyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is lower alkyl, cycloalkylmethyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or lower alkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, lower alkyl, vinyl or arylalkyl.
Structurally the positions of the various amino acids of the compounds of the instant invention may be designated by reference to the octapeptide which is the minimal angiotensinogen sequence cleaved by renin, namely: ##STR3##
A designation for the compounds of this invention is illustrated below. The CAD is considered to occupy the P.sub.1 -P.sub.1 ' positions. For example ##STR4##
The present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
Since HIV protease, like renin, is an aspartyl protease, these compounds can also be used to treat diseases caused by retroviruses including HTLV-I and -III.